1. Field of the Invention
The present invention relates to acyloxypyrrolidine derivatives, to the preparation thereof and to the application thereof in therapeutics.
The compounds according to the present invention exhibit an affinity and selectivity for V1b receptors, or for both V1b and V1a receptors, for arginine-vasopressin (AVP).
2. Description of the Art
AVP is a hormone known for its antidiuretic effect and its effect in the regulation of arterial pressure. It stimulates several types of receptor: V1 (V1a, V1b) and V2. These receptors are located in particular in the liver, the vessels (coronary, renal, cerebral), the platelets, the kidney, the uterus, the adrenal glands, the pancreas, the central nervous system and the pituitary gland. AVP thus exerts cardiovascular, hepatic, pancreatic, antidiuretic and platelet-aggregating effects and effects on the central and peripheral nervous system and on the uterine sphere.
The location of the various receptors is described in: S. JARD et al., Vasopressin and oxytocin receptors: an overview, in Progress in Endocrinology. H. IMURA and K. SHIZURNE ed., Experta Medica, Amsterdam, 1988, 1183–1188, and also in the following articles: J. Lab. Clin. Med., 1989, 114 (6), 617–632 and Pharmacol. Rev., 1991, 43 (1), 73–108.
More particularly, V1a receptors for AVP are located in many peripheral organs and in the brain. They have been cloned, in particular in rats and humans, and they regulate most of the known effects of AVP: platelet aggregation; uterine contractions; vessel contractions; secretion of aldosterone, of cortisol, of CRF (for corticotropin-releasing factor) and of adrenocorticotrophic hormone (ACTH); hepatic glycogenolysis, cell proliferation and the main central effects of AVP (hypothermia, memory, etc.).
V1b receptors were initially identified in the adenohypophysis of various animal species (rats, pigs, bovines, sheep, etc), including in humans (S. JARD et al., Mol. Pharmacol., 1986, 30, 171–177; Y. ARSENIJEVIC et al., J. Endocrinol., 1994, 141, 383–391; J. SCHWARTZ et al., Endocrinology, 1991, 129 (2), 1107–1109; Y. DE KEYSER et al., FEBS Letters, 1994, 356, 215–220), where they stimulate the release of adrenocorticotrophic hormone by AVP and potentiate the effects of CRF on the release of ACTH (G. E. GILLIES et al., Nature, 1982, 299, 355). In the hypothalamus, V1b receptors also induce direct release of CRF (Neuroendocrinology, 1994, 60, 503–508) and are, in these various respects, involved in situations of stress.
These V1b receptors have been cloned in rats, humans and mice (Y. DE KEYSER, FEBS, Letters, 1994, 356, 215–220; T. SUGIMOTO et al., J. Biol. Chem., 1994, 269 (43), 27088–27092; M. SAITO et al., Biochem. Biophys. Res. Commun., 1995, 212 (3), 751–757; S. J. LOLAIT et al., Neurobiology, 1996, 92, 6783–6787; M. A. VENTURA et al., Journal of Molecular Endocrinology, 1999, 22, 251–260) and various studies (in situ hybridization, PCR (polymerase chain reaction), etc.) reveal an ubiquitous location for these receptors in various central tissues, (brain, hypothalamus and adenohypophysis, in particular) and peripheral tissues (kidney, pancreas, adrenals, heart, lungs, intestine, stomach, liver, mesentery, bladder, thymus, spleen, uterus, retina, thyroid, etc.) and in some tumors (hypophyseal, pulmonary, etc.), suggesting a widespread biological and/or pathological role to these receptors and a potential involvement in various diseases.
By way of examples, in rats, studies have shown that AVP, via V1b receptors, regulates the endocrine pancreas by stimulating secretion of insulin and of glucagon (B. LEE et al., Am. J. Physiol. 269 (Endocrinal. Metab. 32): E1095–E1100, 1995) or the production of catecholamines in the adrenal medulla, which is the site of local synthesis of AVP (E. GRAZZINI et al., Endocrinology, 1996, 137 (a), 3906–3914). Thus, in the latter tissue, AVP, via these receptors, would have an essential role in certain types of adrenal pheochromocytomas which secrete AVP and, as a result, induce a large production of catecholamines, causing hypertension resistant to angiotensin II receptor antagonists and to angiotensin-converting enzyme inhibitors. The adrenal cortex is also rich in V1a receptors involved in the production of glucocorticoids and mineralocorticoids (aldosterone and cortisol). Via these receptors, AVP (circulating or locally synthesized) can induce aldosterone production with an efficiency comparable to that of angiotensin II (G. GUILLON et al., Endocrinology, 1995, 136 (3), 1285–1295). Cortisol is a powerful regulator of the production of ACTH, the stress hormone.
Recent studies have also shown that the adrenal glands are capable of directly releasing CRF and/or ACTH via activation of the V1b and/or V1a receptors carried by the cells of the medulla (G. MAZZOCCHI et al., Peptides, 1997, 18 (2), 191–195; E. GRAZZINI et al., J. Clin. Endocrinal. Metab., 1999, 84 (6), 2195–2203).
V1b receptors are also considered to be tumor markers. For example, ACTH-secreting tumors, namely certain pituitary tumors, and certain bronchial carcinomas (small cell lung cancers, SCLC), pancreatic carcinomas, adrenal carcinomas and thyroid carcinomas, inducing Cushing's syndrome in some cases (J. BERTHERAT et al., Eur. J. Endocrinol., 1996, 135, 173; G. A. WITTERT et al., Lancet, 1990, 335, 991–994; G. DICKSTEIN et al., J. Clin. Endocrinol. Metab., 1996, 81 (8), 2934–2941), overexpress V1b receptors. As regards V1a receptors, they are more specific markers for small cell lung cancers (SCLC) (P. J. WOLL et al., Biochem. Biophys. Res. Commun., 1989, 164 (1), 66–73). Thus, the compounds according to the present invention are obvious diagnostic tools and offer a novel therapeutic approach in the proliferation and detection of these tumors, even at an early stage (radiolabelling; SPECT, for Single Photon Emission Computed Tomography; PET Scan, for Positron Emission Tomography Scanner).
The abundant presence of the V1b receptor messenger in the stomach and intestines suggests that AVP is involved, via this receptor, in the release of gastrointestinal hormones such as cholecystokinin, gastrin or secretin (T. SUGIMOTO et al., Molecular cloning and functional expression of V1b receptor gene, in Neurohypophysis: Recent Progress of Vasopressin and Oxytocin Research; T. SAITO, K. KUROKAWA and S. YOSHIDA ed., Elsevier Science, 1995, 409–413).
International patent application WO 01/55130 describes a family of compounds which exhibit an affinity and a selectivity for V1b receptors, or for both V1b and V1a receptors, for arginine-vasopressin.
More particularly, a selective antagonist for V1b receptors, (2S,4R)-1-[5-chloro-1-[(2,4-dimethoxyphenyl)sulfonyl]-3-(2-methoxyphenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-hydroxy-N,N-dimethyl-2-pyrrolidinecarboxamide, the levorotatory isomer (hereinafter referred to as compound A), has been described (WO 01/55130; J. Pharmacol. Exp. Ther., 2002, 300 (3), 1122–1130).
All of the references described herein are incorporated herein by reference in their entirety.